A population of models identifies the interplay between Nav 1.8 conductance and potassium currents as key in regulating human dorsal root ganglion neuron excitability.

The Nav 1.8 sodium channel has a key role in generating repetitive action potentials in nociceptive human dorsal root ganglion neurons. Nav 1.

Development, calibration, and validation of a novel human ventricular myocyte model in health, disease, and drug block.

Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Current models present inconsistencies with experimental data, which limit further progress.

Corrigendum: The Electrogenic Na/K Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study.

[This corrects the article on p. 278 in vol. 8, PMID: 28529489.

Human Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human.

Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine, and Verapamil between Human Trabeculae and Ventricular Models Incorporating Inter-Individual Action Potential Variability.

modeling could soon become a mainstream method of pro-arrhythmic risk assessment in drug development. However, a lack of human-specific data and appropriate modeling techniques has previously prevented quantitative comparison of drug effects between models and recordings from human cardiac preparations. Here, we directly compare changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between populations of human ventricular cell models and human ventricular trabeculae.

The Electrogenic Na/K Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study.

Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions.

Variability in cardiac electrophysiology: Using experimentally-calibrated populations of models to move beyond the single virtual physiological human paradigm.

Physiological variability manifests itself via differences in physiological function between individuals of the same species, and has crucial implications in disease progression and treatment. Despite its importance, physiological variability has traditionally been ignored in experimental and computational investigations due to averaging over samples from multiple individuals. Recently, modelling frameworks have been devised for studying mechanisms underlying physiological variability in cardiac electrophysiology and pro-arrhythmic risk under a variety of conditions and for several animal species as well as human.

Human-based approaches to pharmacology and cardiology: an interdisciplinary and intersectorial workshop.

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analysis, integration and prediction. This paper describes a Workshop on Computational Cardiovascular Science that created an international, interdisciplinary and inter-sectorial forum to define the next steps for a human-based approach to disease supported by computational methodologies.

Experimentally calibrated population of models predicts and explains intersubject variability in cardiac cellular electrophysiology.

Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability.

Defining the limits of single-molecule FRET resolution in TIRF microscopy.

Single-molecule FRET (smFRET) has long been used as a molecular ruler for the study of biology on the nanoscale (∼2-10 nm); smFRET in total-internal reflection fluorescence (TIRF) Förster resonance energy transfer (TIRF-FRET) microscopy allows multiple biomolecules to be simultaneously studied with high temporal and spatial resolution. To operate at the limits of resolution of the technique, it is essential to investigate and rigorously quantify the major sources of noise and error; we used theoretical predictions, simulations, advanced image analysis, and detailed characterization of DNA standards to quantify the limits of TIRF-FRET resolution. We present a theoretical description of the major sources of noise, which was in excellent agreement with results for short-timescale smFRET measurements (<200 ms) on individual molecules (as opposed to measurements on an ensemble of single molecules).